Here we seek to understand the effect of systemically administered Vesicular Stomatitis Virus (VSV) on humans and against metastatic endometrial cancer. This project includes the first-in-human clinical trial of VSV engineered to encode human interferon ? (hIFN?) and the sodium iodide symporter (NIS). hIFN? codes for interferon (IFN) which protects normal cells from VSV effects and NIS enables tumor cells infected with the virus to concentrate various iodine isotopes which can allow for imaging of tumors infected with the virus. The virus being tested in this project is VSV-hIFN?-NIS. We selected VSV as the platform virus for this study because: 1) VSV is a non-lethal, non-human (livestock) virus with mild, if any, symptoms in natural human infections, 2) VSV exposure in the United States is rare with <5% of the population being seropositive, 3) VSV has been safely administered to >7500 humans as the platform virus for HIV and Ebola virus vaccine development, 4) preclinical studies have shown that VSV potently and rapidly kills endometrial cancer cells and tumors, 5) advanced stage and high grade endometrial cancers have been shown to express receptors from the low density lipoprotein receptor (LDLR) family that VSV utilizes for cell infection, 6) mouse and canine studies have established the safety and maximum tolerated dose (MTD) of VSV-hIFN?-NIS in those mammals, 7) mouse studies have shown that VSV-hIFN?-NIS localizes to cancer and can be detected via SPECT/CT imaging, and 8) a phase I trial of a similar virus strain, VSV-hIFN?, is currently being performed in human subjects. This project has incorporated real-time assessments of toxicity, tumor infectivity, and systemic immune responses to the virus and against endometrial cancer. The overarching goal is to generate a comprehensive understanding of the impact of systemic administration of the virus on the immunocompetent human and determine tumor-specific effects of virus infection. The three specific aims to be investigated in this project are: 1. Determine the safety, toxicity and tumor specificity of VSV-hIFN?-NIS when administered intravenously to patients with metastatic endometrial cancer. 2. To determine VSV-hIFN?-NIS replication pharmacokinetics, and shedding after virus administration and perform RNAseq and exome sequencing on tumor and normal tissues to test a novel gene panel as a biomarker for tumor response to the virus. 3. Determine the impact of intravenous VSV-hIFN?-NIS on adaptive immune responses against the virus, endometrial cancer antigens, and immunosuppressive mediators.